PI 3-kinase has been reported to play diverse roles, but its main roles include several basic biological processes including cell proliferation by a platelet-derived growth factor or the like, cytoskeleton regulation, glycometabolism by insulin, neurite extension, immune cell involvement (see Non Patent Literature 1).
PI 3-kinase is an enzyme capable of phosphorylating the hydroxy group at the 3 position of the inositol ring constituting inositol phospholipid, and with phosphatidylinositol, phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-diphosphate as substrates, produces phosphatidylinositol 3-phosphate, phosphatidylinositol 3,4-diphosphate and phosphatidylinositol 3,4,5-triphosphate, respectively. The phospholipid in which the hydroxy group at the 3 position of the inositol ring is phosphorylated by PI 3-kinase serves as the second messenger to activate serine/threonine kinases such as PDK1 and Akt/PKB in the signal transduction pathways via receptor stimulation. Further, PI 3-kinase plays an important role as a controlling factor in membrane transport. PI 3-kinase is classified into three classes, Types I to III, based on the primary structure, the activity regulatory mechanism and substrate specificity. Among the human PI 3Ks family, all PI 3Ks belonging to Class I are composed of a heterodimer comprising a catalytic subunit (molecular weight: about 110 kDa) and a noncatalytic subunit (molecular weight: 50, 55, 85 or 101 kDa) (see Non Patent Literature 2).
PI 3-kinase γ belonging to Class I is expressed only in the hemopoietic system, and the normal expression is found in a gene deficient mouse but a partial suppression of the adaptive immunity in the immune cells is found. More specifically, suppressions, or the like, of the lymphocyte activation and the neutrophilic leukocyte migration (leukocyte chemotaxis) which occur during the immune response are found (see Non Patent Literature 3), suggesting that PI 3-kinase γ is associated with diseases such as rheumatoid arthritis, Crohn's disease, irritable bowel syndrome, Sjoegren's syndrome, multiple sclerosis, systemic lupus erythematosus, asthma, atopic dermatitis, arteriosclerosis, organ transplant rejection, cancer, retinosis, psoriasis, arthrosis deformans, age-related macular degeneration, type II diabetes mellitus, insulin resistance, obesity, fatty liver (NAFLD), non-alcoholic hepatitis (NASH) or hyperlipidemia.
Thus, PI 3-kinase γ inhibitor is considered to be useful to treat or prevent these diseases.
Up to today, the reported PI 3-kinase γ inhibitors include a certain kind of thiazolidinedione derivatives (see Patent Literature 1), pyridopyrimidine-7-one derivatives (see Patent Literature 2), triazolopyridine derivatives (see Patent Literature 3), aminotetrazole derivatives (see Patent Literatures 3 to 6), and 2-aminothiazole derivatives (see Patent Literatures 7 to 15), however, no compound which has the structure of the present invention is disclosed.